title: Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma.
abstract: OBJECTIVE
  There is a clinical need for noninvasive, nonionizing imaging biomarkers of tumor hypoxia and oxygenation. We evaluated the relationship of T1 -weighted oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements to histopathology measurements of tumor hypoxia in a murine glioma xenograft and demonstrated technique translation in human glioblastoma multiforme.
  
  
  METHODS
  Preclinical evaluation was performed in a subcutaneous murine human glioma xenograft (U87MG). Animals underwent OE-MRI followed by dynamic contrast-enhanced MRI (DCE-MRI) and histological measurement including reduced pimonidazole adducts and CD31 staining. Area under the curve (AUC) was measured for the R1 curve for OE-MRI and the gadolinium concentration curve for DCE-MRI. Clinical evaluation in five patients used analogous imaging protocols and analyses.
  
  
  RESULTS
  Changes in AUC of OE-MRI (AUCOE ) signal were regionally heterogeneous across all U87MG tumors. Tumor regions with negative AUCOE typically had low DCE-MRI perfusion, had positive correlation with hypoxic area (P = 0.029), and had negative correlation with vessel density (P = 0.004). DCE-MRI measurements did not relate to either hypoxia or vessel density in U87MG tumors. Clinical data confirmed comparable signal changes in patients with glioblastoma.
  
  
  CONCLUSIONS
  These data support further investigation of T1 -weighted OE-MRI to identify regional tumor hypoxia. The quantification of AUCOE has translational potential as a clinical biomarker of hypoxia.
authors.affiliation: Centre for Imaging Sciences, The University of Manchester, Manchester, UK; University of Manchester Biomedical Imaging Institute, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK.
authors.forename: Inna V
authors.initials: IV
authors.lastname: Linnik
authors.forename: Marietta L J
authors.initials: ML
authors.lastname: Scott
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Holliday
authors.forename: Neil
authors.initials: N
authors.lastname: Woodhouse
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
authors.forename: James P B
authors.initials: JP
authors.lastname: O'Connor
authors.forename: Hervé
authors.initials: H
authors.lastname: Barjat
authors.forename: Carsten
authors.initials: C
authors.lastname: Liess
authors.forename: Jose
authors.initials: J
authors.lastname: Ulloa
authors.forename: Helen
authors.initials: H
authors.lastname: Young
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Hodgkinson
authors.forename: Tim
authors.initials: T
authors.lastname: Ward
authors.forename: Darren
authors.initials: D
authors.lastname: Roberts
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Mills
authors.forename: Gerard
authors.initials: G
authors.lastname: Thompson
authors.forename: Giovanni A
authors.initials: GA
authors.lastname: Buonaccorsi
authors.forename: Susan
authors.initials: S
authors.lastname: Cheung
authors.forename: Alan
authors.initials: A
authors.lastname: Jackson
authors.forename: Josephine H
authors.initials: JH
authors.lastname: Naish
authors.forename: Geoff J M
authors.initials: GJ
authors.lastname: Parker
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D010092:Oximetry / Q000379:methods*; D010100:Oxygen / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D014408:Biomarkers, Tumor; D010100:Oxygen
keywords: hypoxia; magnetic resonance imaging; oxygen-enhanced MRI; oxygenation